Synaptic function of BK channel-interacting proteins

BK 通道相互作用蛋白的突触功能

• 批准号: 10712011
• 负责人: ZHAO-WEN WANG
• 金额: $ 39.17万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10712011
• 关键词: Abeta synthesis; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animal Model; Award; Brain; Caenorhabditis elegans; Calcium; Clinical Trials; Early Onset Familial Alzheimer' s Disease; Endoplasmic Reticulum; Enhancers; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Hippocampus; Human; Knock-out; Knowledge; Link; Mass Spectrum Analysis; Messenger RNA; Molecular; Mus; Mutation; Nematoda; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Parents; Pathogenesis; Pattern; Persons; Phenotype; Play; Property; Proteins; Receptor Gene; Research; Role; Ryanodine Receptor Calcium Release Channel; Senile Plaques; Synapses; Synaptic Receptors; Synaptic Transmission; System; Testing; Translations; Work; abeta accumulation; brain tissue; candidate identification; genetic regulatory protein; inhibitor; knock-down; large-conductance calcium-activated potassium channels; mutant; neurotransmitter release; postsynaptic; presenilin; presynaptic; receptor expression; receptor function; synaptic function; transcriptome sequencing

Alzheimer’s disease (AD) is a neurodegenerative disorder inflicting many people. Most cases of early-onset familial AD are linked to mutations of presenilins. Previous studies on presenilins have focused on their roles in the generation of amyloid β (Aβ) because accumulation of Aβ plaques in brain tissue is generally considered the primary cause of AD. However, the amyloid hypothesis is being questioned because all anti-amyloid clinical trials have failed. Therefore, it is necessary to explore other potential mechanisms of presenilin function in AD. Among the known effects of presenilin mutations are reduced neurotransmitter release and calcium dyshomeostasis, which are both putative underlying mechanisms of AD. It is known that mutations of presenilins cause reduced neurotransmitter release and calcium dyshomeostasis, which are associated with and potentially caused by decreased ryanodine receptor expression. However, it is unknown how presenilins regulate ryanodine receptors. This proposal is to test the hypothesis that presenilins regulate ryanodine receptor expression by acting through some other regulatory proteins. The nematode Caenorhabditis elegans is used as an animal model to identify the putative regulatory proteins because many cellular mechanisms in mammalian systems, including the roles of presenilins in synaptic and ryanodine receptor function, are conserved in worms. The specific aims of this proposal are: 1) identify candidates for the putative regulatory proteins of ryanodine receptor expression by mass spectrometry and RNA-seq, and 2) determine whether the identified proteins are required for presenilins’ roles in neurotransmitter release and ryanodine receptor expression. Our long-term goal is to illustrate whether and how reduced neurotransmitter release and ryanodine receptor function play a role in the pathogenesis of AD caused by presenilin mutations.

阿尔茨海默病（AD）是一种神经退行性疾病，困扰着许多人。大多数病例早发 家族性 AD 与早老素突变有关。先前对早老素的研究主要集中在它们在 β 淀粉样蛋白 (Aβ) 的产生，因为脑组织中 Aβ 斑块的积累通常被认为是 AD 的主要原因。然而，淀粉样蛋白假说受到质疑，因为所有抗淀粉样蛋白临床试验 已经失败了。因此，有必要探索早老素在 AD 中发挥作用的其他潜在机制。之中 早老素突变的已知影响是神经递质释放减少和钙稳态失调， 这都是 AD 的假定潜在机制。众所周知，早老素的突变会导致 神经递质释放和钙稳态失衡，与以下因素相关并可能由其引起： 兰尼碱受体表达减少。然而，早老素如何调节兰尼碱受体尚不清楚。 该提案旨在检验早老素通过作用调节兰尼碱受体表达的假设 一些其他调节蛋白。使用线虫秀丽隐杆线虫作为动物模型来鉴定 假定的调节蛋白，因为哺乳动物系统中的许多细胞机制，包括作用 早老素在突触和兰尼碱受体功能中的作用在蠕虫中是保守的。本次活动的具体目标 建议是：1）通过质量鉴定兰尼碱受体表达的假定调节蛋白的候选者 光谱测定和 RNA-seq，2) 确定所鉴定的蛋白质是否是早老素作用所必需的 神经递质释放和兰尼碱受体表达。我们的长期目标是阐明是否以及 神经递质释放和兰尼碱受体功能减少如何在 AD 发病机制中发挥作用 由早老素突变引起。